JP2022511785A - Compositions and Methods for Treating Dementia - Google Patents
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Abstract
本発明は、認知症、特にアルツハイマー病をベニクスノキタケ子実体の抽出物またはその活性成分で処置する方法を提供する。また、本発明では、認知症、特にアルツハイマー病を処置するための医薬を製造するための、ベニクスノキタケ(Antrodia camphorate)の抽出物またはその活性成分の使用が提供される。The present invention provides a method for treating dementia, particularly Alzheimer's disease, with an extract of Camphor tree substance or an active ingredient thereof. The present invention also provides the use of an extract of Antrodia camphorate or an active ingredient thereof for producing a pharmaceutical for treating dementia, particularly Alzheimer's disease.
Description
（関連出願の相互参照）
本出願は、2018年11月28日出願の米国仮特許出願62/772,211の利益および優先権を主張し、この全内容は引用により本明細書に包含される。
(Mutual reference of related applications)
This application claims the interests and priorities of US provisional patent application 62 / 772,211 filed November 28, 2018, the entire contents of which are incorporated herein by reference.
（発明の分野）
本発明は、認知症を処置する方法に関する。
(Field of invention)
The present invention relates to a method of treating dementia.
アルツハイマー病(AD)は、進行性の認知低下、神経原線維変化、アミロイドプラーク、神経炎症および成体神経新生の低下を特徴とする(1-3)。アミロイドβ(Aβ)は、アミロイド前駆体タンパク質(APP)の加工により形成されるペプチドであり、ADの病理の主要な開始因子の一つと考えられている。アミロイド仮説では、ADは、Aβの産生と除去の不均衡が原因である提唱されており(1)、その結果、中枢神経系(CNS)において、単量体、オリゴマー、不溶性の線維状のAβ量が増加し、その後、Aβプラークの形成、神経炎症、酸化的ストレスを誘発するとされる(4)。 Alzheimer's disease (AD) is characterized by progressive cognitive decline, neurofibrillary tangles, amyloid plaques, neuroinflammation and decreased adult neurogenesis (1-3). Amyloid β (Aβ) is a peptide formed by processing amyloid precursor protein (APP) and is considered to be one of the major initiation factors for AD pathology. The amyloid hypothesis suggests that AD is due to an imbalance in the production and removal of Aβ (1), resulting in monomeric, oligomeric, insoluble fibrous Aβ in the central nervous system (CNS). It is said to increase in volume and then induce Aβ plaque formation, neuroinflammation, and oxidative stress (4).
成体の海馬における神経新生が認知機能に主要な役割を果たすことを示す証拠が増えている(5)。オリゴマーAβ、可溶性APPα(sAPP)αおよびAPP細胞内ドメイン(AICD)などのAPP代謝物は、成体の海馬における神経新生に影響を与えるヒト神経幹細胞の性質を調節することが見出されている(6,7)。他方で、活性化グリアによって産生されるIL-1β、TNF-γおよびIL-6などの炎症性サイトカインは、成体の海馬における神経新生の過程を調節することもある(8-10)。 There is increasing evidence that neurogenesis in the adult hippocampus plays a major role in cognitive function (5). APP metabolites such as oligomer Aβ, soluble APPα (sAPP) α and APP intracellular domain (AICD) have been found to regulate the properties of human neural stem cells that affect neurogenesis in the adult hippocampus ( 6,7). On the other hand, inflammatory cytokines such as IL-1β, TNF-γ and IL-6 produced by activated glia may also regulate the process of neurogenesis in the adult hippocampus (8-10).
APPswe/PS1dE9マウスモデル(APP/PS1)は、Swedish変異ヒトAPP695とエクソン9が欠失したヒト変異型プレセニリン1(PS1)を共発現したものであり(11)、これは、脳内のアミロイドプラークの蓄積、コリン作動系の衰退、および探索行動や空間的な記憶の障害など、AD様病理学的・行動学的変化を示す(12)。APP/PS1マウスにおけるAβ産生とプラーク形成の増加は、3～5ヶ月齢という早い時期に起こることが示されており(13)、6ヶ月齢では、空間的な学習・記憶の障害が観察されている(14-15)。さらに、3～6ヶ月齢のAPP/PS1マウスでは、神経新生が損なわれていることも見出されている(16)。 The APPswe / PS1dE9 mouse model (APP / PS1) co-expressed the Swedish mutant human APP695 and the exon 9-deficient human mutant presenilin 1 (PS1) (11), which is an amyloid plaque in the brain. AD-like pathological and behavioral changes such as accumulation of amyloid, decline of cholinergic system, and impaired exploratory and spatial memory (12). Increased Aβ production and plaque formation in APP / PS1 mice have been shown to occur as early as 3-5 months of age (13), with spatial learning and memory impairment observed at 6 months of age. (14-15). Furthermore, it has been found that neurogenesis is impaired in APP / PS1 mice aged 3 to 6 months (16).
副作用がなく、毒性の低いADを処置するための医薬の開発が求められている。 There is a need to develop a drug for treating AD with no side effects and low toxicity.
本発明の目的は、認知症を処置する方法であって、それを必要とする患者に、ベニクスノキタケ(Antrodia camphorata、樟芝)子実体の抽出物を活性成分として投与することを含む方法を提供することである。 An object of the present invention is a method for treating dementia, which comprises administering an extract of Antrodia camphorata fruiting body to a patient in need thereof as an active ingredient. To provide.
別の目的において、本発明は、認知症を処置するための医薬を製造するためのベニクスノキタケ子実体の抽出物の使用を提供する。 For another object, the present invention provides the use of an extract of Camphor tree substance to produce a pharmaceutical for treating dementia.
特に、ベニクスノキタケ子実体の抽出物は、以下、ARH003と称する皿で培養されているベニクスノキタケ(Antrodia camphorate)子実体の抽出物、または以下、ARH004と称する切断木で培養されているベニクスノキタケ(Antrodia camphorate)子実体の抽出物である。 In particular, the extract of the fruiting body of Antrodia camphorate is the extract of the fruiting body of Antrodia camphorate, which is cultivated in a dish called ARH003, or the extract of the fruiting body of Antrodia camphorate, which is cultivated in a cut tree called ARH004. Bamboo (Antrodia camphorate) An extract of fruiting bodies.
本発明の一実施例において、ベニクスノキタケ子実体の抽出物は、ベニクスノキタケ(Antrodia camphorate)子実体の抽出物を水または有機溶媒で抽出することによって調製される。 In one embodiment of the invention, the extract of Antrodia camphorate fruiting body is prepared by extracting the extract of Antrodia camphorate fruiting body with water or an organic solvent.
本発明の一特定の実施例において、ベニクスノキタケ子実体の抽出物は、
からなる群から選択される、一つまたはそれ以上の活性成分としての化合物を含む。
In one particular embodiment of the invention, the extract of Camphor tree substance is
Contains one or more compounds as active ingredients selected from the group consisting of.
本発明のいくつかの特定の実施例において、化合物は、
他方で、本発明は、認知症を処置する方法であって、それを必要とする対象に、上記の一つまたはそれ以上の活性化合物を投与することを含む方法を提供する。 On the other hand, the present invention provides a method for treating dementia, which comprises administering one or more of the above active compounds to a subject in need thereof.
本発明はまた、認知症を処置するための医薬を製造するための、上記の化合物の使用を提供する。 The present invention also provides the use of the above compounds for producing a pharmaceutical for treating dementia.
本発明の一実施態様において、認知症はADである。 In one embodiment of the invention, dementia is AD.
されなる一態様において、本発明は、Aβプラークの形成およびグリア細胞の活性化を抑制する方法であって、それを必要とする対象に、上記のベニクスノキタケ子実体の抽出物を投与することを含む方法を提供する。 In one embodiment of the above, the present invention is a method for suppressing the formation of Aβ plaque and the activation of glial cells, wherein the above-mentioned extract of Camphor tree substance is administered to a subject in need thereof. Provide a method to include.
また、Aβプラークの形成およびグリア細胞の活性化を抑制するための医薬を製造するための、ベニクスノキタケ子実体の抽出物の使用を提供する。 Also provided is the use of an extract of the camphor tree substance to produce a pharmaceutical for suppressing the formation of Aβ plaques and the activation of glial cells.
されなる一態様において、本発明は、本発明は、Aβプラークの形成およびグリア細胞の活性化を抑制する方法であって、それを必要とする対象に、一つまたはそれ以上の上記の化合物を投与することを含む方法を提供する。 In one aspect thereof, the present invention is a method for suppressing the formation of Aβ plaque and the activation of glial cells, wherein one or more of the above compounds are provided to a subject in need thereof. Provided are methods involving administration.
また、本発明は、Aβプラークの形成およびグリア細胞の活性化を抑制するための医薬を製造するための、上記の化合物の使用を提供する。 The present invention also provides the use of the above compounds for the manufacture of a pharmaceutical for suppressing the formation of Aβ plaques and the activation of glial cells.
さらなる一態様において、本発明は、記憶力を向上させる方法であって、それを必要とする対象に、ベニクスノキタケ子実体の抽出物を投与することを含む方法を提供する。 In a further aspect, the invention provides a method of improving memory, comprising administering to a subject in need thereof an extract of the camphor tree substance.
また、本発明は、記憶力を向上させるための医薬を製造するための、上記の化合物の使用を提供する。 The present invention also provides the use of the above compounds for producing a pharmaceutical to improve memory.
本発明において、本発明による抽出物または化合物は、認知症の処置、記憶障害の改善および/または記憶力の向上の効能を提供する。 In the present invention, the extract or compound according to the present invention provides the efficacy of treating dementia, ameliorating memory impairment and / or improving memory.
前述の一般的な説明と以下の詳細な説明の両方は、例示的かつ説明的なものに過ぎず、本発明を制限するものではないことを理解されたい。 It should be understood that both the general description above and the detailed description below are illustrative and descriptive and do not limit the invention.
前述の概要、および以下の発明の詳細な説明は、添付の図面と併せて読むと、よりよく理解されるであろう。本発明を説明する目的で、現在好ましいとされている実施態様が図面に示されている。 The above overview and detailed description of the invention below will be better understood when read in conjunction with the accompanying drawings. For purposes of illustrating the invention, currently preferred embodiments are shown in the drawings.
図面において、
（本発明の詳細な説明）
特に定義されていない限り、本明細書で使用されているすべての技術用語および科学用語は、本発明が属する技術分野の当業者が一般的に理解しているものと同じ意味を有する。
(Detailed description of the present invention)
Unless otherwise defined, all technical and scientific terms used herein have the same meanings commonly understood by those skilled in the art to which the present invention belongs.
本発明は、認知症を処置する方法であって、それを必要とする患者に、ベニクスノキタケ子実体の抽出物を活性成分として投与する方法を提供する。 The present invention provides a method for treating dementia, in which an extract of camphor tree substance is administered as an active ingredient to a patient in need thereof.
ベニクスノキタケ(AC)は、台湾では「niu chang-chih」または「niu-chang-ku」と称さており、台湾固有のキノコである(17)。ACは、1773年以前から民間療法として、腱の捻挫および筋肉損傷、恐れる精神状態、インフルエンザもしくは風邪、頭痛、発熱および多くの内部関連疾患(internally affiliated diseases)に広く使用されてきた(18)。ACの異なる抽出物および化合物は、神経保護(19、20)、肝臓保護、抗高血圧、抗脂質異常、抗遺伝毒性、抗血管形成、抗微生物性、抗癌、抗炎症性、抗酸化、抗ウイルス、および免疫調節活性(21、22)を含めた、さまざまな生物学的活性を示すことが見出されている。 Camphor tree (AC) is called "niu chang-chih" or "niu-chang-ku" in Taiwan and is a mushroom peculiar to Taiwan (17). AC has been widely used as a folk remedy since 1773 for tendon sprains and muscle injuries, feared mental states, influenza or colds, headaches, fever and many internally affiliated diseases (18). Different extracts and compounds of AC include neuroprotection (19, 20), liver protection, antihypertension, antilipid abnormalities, antigenetic toxicity, antiangiogenic, antimicrobial, anticancer, antiinflammatory, antioxidant, antibacterial. It has been found to exhibit a variety of biological activities, including viral and immunomodulatory activity (21, 22).
特に、ベニクスノキタケ子実体の抽出物は、皿で培養されているベニクスノキタケ(Antrodia camphorate)子実体の抽出物(ARH003)または切断木で培養されているベニクスノキタケ(Antrodia camphorate)子実体の抽出物(ARH004)である。 In particular, the extract of the fruiting body of Antrodia camphorate is the extract of the fruiting body of Antrodia camphorate cultured in a dish or the fruiting body of Antrodia camphorate cultured in a cut tree. It is an extract (ARH004).
本発明において、組成物は、認知症、特にADの処置に有効であることが証明されている。 In the present invention, the compositions have been proven to be effective in treating dementia, especially AD.
したがって、本発明は、認知症、特にADを処置するための医薬を製造するための抽出物、特に皿で培養されているベニクスノキタケ子実体の抽出物、すなわち、ARH003および/またはARH004の使用を提供する。 Therefore, the present invention uses the use of extracts for producing pharmaceuticals for the treatment of dementia, in particular AD, especially extracts of Camphor tree varieties cultured in dishes, ie ARH003 and / or ARH004. offer.
本発明において、抽出物ARH003/ARH004は、
本発明の好ましい実施態様において、活性化合物は、
したがって、本発明は、認知症を処置する方法であって、それを必要とする対象に有効量の上記の活性化合物を投与することを含む方法を提供する。 Accordingly, the present invention provides a method of treating dementia comprising administering to a subject in need thereof an effective amount of the above active compound.
本明細書で使用される用語「治療有効量」とは、そのような量を投与されていない対応する対象と比較して、疾患、障害もしくは副作用の処置、治癒、予防または改善、あるいは疾患または障害の進行速度の低下に有効な医薬品の量を意味する。また、この用語は、その範囲内に、正常な生理学的機能を高めるのに有効な量も含む。 As used herein, the term "therapeutically effective amount" means the treatment, cure, prevention or amelioration of a disease, disorder or side effect, or disease or It means the amount of medicine that is effective in slowing the progression of the disorder. The term also includes, within that range, an amount effective in enhancing normal physiological function.
治療に使用する場合、治療有効量の化合物は、投与のための医薬組成物に製剤化される。したがって、本発明は、ARH003および/またはARH004の治療有効量ならびに一つまたはそれ以上の薬学的に許容できる担体をさらに含む医薬組成物を提供する。 When used therapeutically, a therapeutically effective amount of the compound is formulated into a pharmaceutical composition for administration. Accordingly, the invention provides a pharmaceutical composition further comprising a therapeutically effective amount of ARH003 and / or ARH004 and one or more pharmaceutically acceptable carriers.
本明細書で使用される用語「製薬的に許容できる担体」とは、製剤の他の成分と互換性があり、医薬組成物を投与される対象に有害でない意味で許容できる担体、希釈剤または賦形剤を意味する。この分野で一般的に知られている、あるいは使用されているあらゆる担体、希釈剤または賦形剤は、医薬製剤の要求に応じて本発明で使用され得る。 As used herein, the term "pharmaceutically acceptable carrier" is a carrier, diluent or carrier that is compatible with the other ingredients of the pharmaceutical product and is not harmful to the subject to whom the pharmaceutical composition is administered. Means an excipient. Any carrier, diluent or excipient commonly known or used in the art can be used in the present invention as required by pharmaceutical formulations.
本発明によれば、医薬組成物は、経口、直腸、経鼻、局所、膣または非経腸経路を含むがこれらに限定されない、いずれかの適切な経路による投与に適合させることができる。本発明の一特定の例において、医薬組成物は経口投与に製剤化される。このような製剤は、薬学の分野で知られているいずれかの方法によって調製できる。 According to the present invention, the pharmaceutical composition can be adapted for administration by any suitable route including, but not limited to, oral, rectal, nasal, topical, vaginal or non-enteral routes. In one particular example of the invention, the pharmaceutical composition is formulated for oral administration. Such a formulation can be prepared by any method known in the field of pharmacy.
本発明は、以下の実施例によってさらに説明されますが、これらの実施例は、限定ではなく実証の目的で提供される。 The invention is further described by the following examples, which are provided for demonstrative purposes without limitation.
材料および方法
1．材料
BrdU、ギ酸およびThioflavin Sは、Sigma-Aldrich(St Louis, MO, USA)から購入した。一般的な化学製品は、Sigma-Aldrich(St Louis, MO, USA)またはMerck(Darmstadt, Germany)から購入した。
material and method
1. 1. material
BrdU, formic acid and Thioflavin S were purchased from Sigma-Aldrich (St Louis, MO, USA). Common chemicals were purchased from Sigma-Aldrich (St Louis, MO, USA) or Merck (Darmstadt, Germany).
2.ベニクスノキタケ子実体の抽出(ARH003およびARH004の調製)
ARH003は、皿で培養されているベニクスノキタケから調製した。子実体(300g)およびARH004は、切断木で培養されているベニクスノキタケ(ARH004)から調製した。子実体を、95%エタノールで熱還流した。エタノール溶液を真空に濃縮し、褐色の抽出物(60g)を得た。
2. Extraction of Camphor tree substance (Preparation of ARH003 and ARH004)
ARH003 was prepared from Benix camphor tree cultivated in a dish. Fruiting bodies (300 g) and ARH004 were prepared from Benix nokitake (ARH004) cultured in cut trees. Fruiting bodies were heat refluxed with 95% ethanol. The ethanol solution was concentrated in vacuo to give a brown extract (60 g).
3．管理および投与
国家中医学研究所の機関内動物保護および使用委員会承認の動物プロトコール(IACUC No:106-417-4)。動物とその保護に関するすべての実験操作は、米国国立衛生研究所(United States National Institutes of Health, NIH)により発行された実験動物のケアと使用に関するガイドに従って実施した。APP/PS1は、Jackson試験室(No.005864)から購入した。飼育の性比は、一つのケージに1匹の雄性と2匹の雌性であった。野生型のシブリング(sibling)マウスとADトランスジェニックの雌性C57BL/6Jマウスを用いて実験を行った。動物は、室温(24±1℃)および湿度(55～65％)、12：12時間(07：00～19：00)の明暗周期下で管理された環境で飼育した。すべての動物実験操作は、実験動物の保護と使用に関するガイド(NIH)に基づいて実施した。APP/PS1は、Jackson試験室(No.005864)から購入した。雌性トランスジェニックマウスおよび雄性野生型のシブリングを用いて飼育した。動物は、温度(24±1℃)および湿度(55～65%)下で飼育した。明暗周期は、12:12時間(07:00～19:00)にした。すべてのマウスに、市販の齧歯類用の普通の餌、および自由引水を提供した。治療効果を研究するために、3ヶ月齢の雄性および雌性のAPP/PS1マウスの両方に、ビヒクル(n=7 雄性およびn=8 雌性)またはARH003もしくはARH004(100mg kg-1日-1、n=7 雄性およびn=10 雌性)を4ヶ月間経口胃管栄養法(oral gavage)で投与した。
3. 3. Management and Administration Animal Protocol approved by the National Institute of Traditional Chinese Medicine Institutional Animal Protection and Use Committee (IACUC No: 106-417-4). All experimental operations related to animals and their protection were performed according to the guide to the care and use of laboratory animals published by the United States National Institutes of Health (NIH). APP / PS1 was purchased from Jackson Laboratory (No.005864). The sex ratios for rearing were one male and two females in one cage. Experiments were performed using wild-type sibling mice and AD transgenic female C57BL / 6J mice. Animals were bred in a controlled environment at room temperature (24 ± 1 ° C.) and humidity (55-65%), with a light-dark cycle of 12:12 hours (07: 00-19: 00). All animal experiment operations were performed based on the Guide to the Protection and Use of Laboratory Animals (NIH). APP / PS1 was purchased from Jackson Laboratory (No.005864). They were bred using female transgenic mice and male wild-type siblings. Animals were bred under temperature (24 ± 1 ° C) and humidity (55-65%). The light-dark cycle was 12:12 hours (07: 00-19: 00). All mice were provided with a commercial rodent normal diet and free water withdrawal. To study the therapeutic effect, vehicle (n = 7 male and n = 8 female) or ARH003 or ARH004 (100 mg kg -1 day -1 , n) in both male and female APP / PS1 mice aged 3 months. (= 7 male and n = 10 female) were administered by oral gastrointestinal feeding (oral gavage) for 4 months.
4．組織処理
マウスを、麻酔をかけた後、経心食塩水の灌流で犠牲にした。マウスの脳を摘出し、4℃下、4％ホルムアルデヒドに一晩浸し、凍結保護した。続いて、脳組織を30μmの厚さに切った。各脳において、頭蓋骨の前項を大体-1.58から-1.82に跨る3枚のスライドを、染色と分析に使用した。
Four. Tissue-treated mice were sacrificed by transcardiac saline perfusion after anesthesia. Mice brains were removed, soaked in 4% formaldehyde overnight at 4 ° C, and cryoprotected. Subsequently, the brain tissue was cut to a thickness of 30 μm. In each brain, three slides, approximately spanning the anterior section of the skull from -1.58 to -1.82, were used for staining and analysis.
5．Amylo-Glo染色
線維性アミロイドの染色は、メーカー(Biosensis Inc., Thebarton, South Australia)の説明に従ってAmylo-Gloを用いて行った
Five. Amylo-Glo staining Fibrotic amyloid was stained with Amylo-Glo according to the manufacturer's instructions (Biosensis Inc., Thebarton, South Australia).
6．免疫組織化学
先に述べたように、免疫組織化学を行った(39)。簡単に説明すると、切片を、1％ウシ血清アルブミン(BSA)、3％正常ロバ血清、0.3％Triton X-100を含有するリン酸緩衝化食塩水(PBS)で1時間ブロックした。その後、4℃下で以下の物質を含有するPBS中でインキュベートした：1％BSA、1％正常ロバ血清、0.3％Triton X-100、ならびにAβ1-16に対するマウスモノクローナル抗体(AB10, Millipore, MAB5208, 2757889)、およびグリア線維酸性タンパク質に対するウスモノクローナル抗体(GFAP, Millipore, MAB5804, 1990686)を含む一次抗体；ならびに抗イオン化カルシウム結合アダプター分子-1(Iba-1)抗体に対するヤギポリクローナル抗体(abcam, ab5076, GR268568-3)。続いて、切片を室温で、Hoechst33258(Invitrogen, 2μg ml-1)、フルオレセインイソチオシアネートまたはrhodamine red X(RRX)共役ロバ抗マウスIgG、RRX共役ロバ抗ウサギIgGまたはAlexa Fluor 647共役ロバ抗ヤギIgG(Jackson ImmunoResearch, 705-605-147)を含有する抗体希釈緩衝液中で2時間インキュベートした。0.01%Triton X-100を含有するPBSで洗浄した後、切片をAqua Poly/Mount(Polyscience Inc., Warrington, PA, USA)にはめ込み、Zeiss LSM 780共焦点顕微鏡(Jena, Germany)を用いて顕微鏡的分析を行った。体表的な共焦点画像は、最大投射で10μm深さであった。ImageJソフトウェアを用いてアミロイドプラークの定量化を行った。総面積に対するAB10-反応性またはThS陽性面積の比によってアミロイドプラークの負荷を計算した。
6. Immunohistochemistry As mentioned earlier, immunohistochemistry was performed (39). Briefly, sections were blocked with phosphate buffered saline (PBS) containing 1% bovine serum albumin (BSA), 3% normal donkey serum, and 0.3% Triton X-100 for 1 hour. Then incubated in PBS containing the following substances at 4 ° C: 1% BSA, 1% normal donkey serum, 0.3% Triton X-100, and mouse monoclonal antibodies against Aβ1-16 (AB10, Millipore, MAB5208, 2757889), and primary antibodies including Us monoclonal antibody against glial fiber acidic protein (GFAP, Millipore, MAB5804, 1990686); and goat polyclonal antibody against anti-ionized calcium binding adapter molecule-1 (Iba-1) antibody (abcam, ab5076, GR268568-3). Subsequently, the sections were sectioned at room temperature with Hoechst 33258 (Invitrogen, 2 μg ml -1 ), fluorescein isothiocyanate or rhodamine red X (RRX) conjugated donkey anti-mouse IgG, RRX conjugated donkey anti-rabbit IgG or Alexa Fluor 647 conjugated donkey anti-goat IgG ( Incubated for 2 hours in an antibody dilution buffer containing Jackson ImmunoResearch, 705-605-147). After washing with PBS containing 0.01% Triton X-100, sections are fitted into Aqua Poly / Mount (Polyscience Inc., Warrington, PA, USA) and microscoped using a Zeiss LSM 780 confocal microscope (Jena, Germany). Analysis was performed. The body surface confocal image was 10 μm deep at maximum projection. Amyloid plaques were quantified using ImageJ software. Amyloid plaque loading was calculated by the ratio of AB10-reactive or ThS positive areas to total area.
7．穴掘り(Burrowing)テストおよび巣作りテスト
マウスを、70日間の強制経口投与後、前記のように(46)、穴掘りテストの評価を行い、若干の補正を加えた。要するに、70日目に群ケージで練習を行い、77日目と80日目には個別テストを行った。マウスを、薄層の床敷を備えた新しいケージで飼育し、続いて翌日の16：00時に餌ペレット230ｇを含むシリンダーをケージに入れた。最後に、2時間後と一晩後にシリンダー内に残った餌ペレットの重量を測定した。2回目の個別テストでは、餌ペレットに対する穴掘りにおける2時の測定を結果に示した。
7. 7. Burrowing test and nesting test Mice were orally administered for 70 days and then evaluated as described above (46) for the burrowing test with some corrections. In short, practice was performed in the group cage on the 70th day, and individual tests were performed on the 77th and 80th days. Mice were housed in a new cage with a thin bedding, followed by a cylinder containing 230 g of food pellets at 16:00 the next day. Finally, the weight of the bait pellets remaining in the cylinder after 2 hours and overnight was weighed. The second individual test showed results at 2 o'clock in digging for bait pellets.
穴掘りテストの一日後に、前記のように巣作りテストを行った(35)。要するに、暗サイクルの1時間前に2つのネストレット(5g)をケージに入れ、続いて、一晩後に巣作りスコアと細断されていないネストレットの重量を測定した。6段階の尺度を用いて巣の構造について採点した(40)。スコア0はネストレットが乱されていないこと、1はネストレットが乱されたが、巣材がケージ内の巣作り位置に集まっていないこと、2は平たい巣(flat nest)、3はカップの巣(cup nest)、4は不完全なドーム、5は完全で密閉されたドーム、を指す。
One day after the digging test, a nesting test was performed as described above (35). In short, two nestlets (5 g) were placed in
8．モリス水迷路テスト
90日間の処理後、前記のように(41,42)、モリス水迷路(MWM)テストを用いて空間記憶パホーマンスを評価し、若干の修正を加えた。要するに、水迷路装置は、直径120cm、深さ40cmの円形プールからなっており、プラットフォーム(直径10cm)を覆うように水(温度22～24℃)を20cmの高さまで入れた。無毒の白色の塗料を追加することにより、プラットフォームを不透明な水の表面から1cm下に沈ませた。記述的なデータ収集について、プールを四つの等しい象限概念的に分けた。コンピューター化ビデオ画像解析システム(Ethovision, Noldus Information Technology Inc, USA)を用いて、迷路の白色の背景における黒色のマウスの水泳経路を記録した。
8. Morris water maze test
After 90 days of treatment, spatial memory performance was assessed using the Morris Water Maze (MWM) test as described above (41,42) with minor modifications. In short, the water maze device consisted of a circular pool with a diameter of 120 cm and a depth of 40 cm, with water (temperature 22-24 ° C) filled to a height of 20 cm so as to cover the platform (
空間記憶テストを行い、マウスの空間記憶パホーマンスを研究した。全てのマウスをMWMで6日間訓練させた。プラットフォームは、始終南西方向の中央に設置した。マウスをそれぞれ、1日に4回の試験でプラットフォームを見つけるように訓練させ、試験間の間隔は20分であった。各試験において、セミ・ランダム・スケジュールに従って、マウスをプールの壁に面した、水中の3つの固定位置のうち1つに静かに降ろした。マウスが60秒以内に成功しなかった場合は、それをプラットフォームまで助けた。各試験の終了時に、マウスを、プラットフォームを見つけたかどうかにかかわらず、30秒間プラットフォーム上に留まることを許容した。各試験において、プラットフォームを見つける逃避潜時を測定し、4試験にわたって平均値取った。 A spatial memory test was performed to study the spatial memory performance of mice. All mice were trained in MWM for 6 days. The platform was installed in the center of the southwest direction from beginning to end. Each mouse was trained to find the platform in four tests per day, with an interval of 20 minutes between tests. In each study, mice were gently lowered into one of three fixed positions in the water facing the wall of the pool according to a semi-random schedule. If the mouse did not succeed within 60 seconds, it helped it to the platform. At the end of each test, mice were allowed to stay on the platform for 30 seconds regardless of whether they found the platform. In each test, the escape latency to find the platform was measured and averaged over 4 tests.
空間プローブテストを行い、記憶の程度を評価した(43)。標的象限で費やされた時間は、訓練期間中の学習後に得られた記憶の程度を表している。6日間の習得訓練後の翌日に、90秒プローブ試験(一回の試験はプラットフォームなし)を評価した。マウスを、開始位置から、プール中の前のプラットフォーム象限の反対側の象限の位置に配置した。マウスが前のプラットフォームの位置を横断した回数と、前のプラットフォームの象限で費やした時間を90秒間記録した。MWMのプローブ試験バージョンで、中央ゾーンと外縁ゾーンで費やされた時間の百分比を考察した。外縁ゾーンは、壁と壁から10cm離れている円の間の領域と定義されている(44)。
A spatial probe test was performed to assess the degree of memory (43). The time spent in the target quadrant represents the degree of memory gained after learning during the training period. The day after 6 days of learning training, a 90-second probe test (one test without platform) was evaluated. Mice were placed in the opposite quadrant of the previous platform quadrant in the pool from the starting position. The number of times the mouse crossed the position of the previous platform and the time spent in the quadrant of the previous platform were recorded for 90 seconds. In the probe test version of MWM, we considered the percentage of time spent in the central zone and the outer edge zone. The outer edge zone is defined as the area between the walls and the
9．統計分析
結果は平均値±平均標準誤差(SEM)で表し、GraphPad Prism 5ソフトウェアを用いて統計分析処理した。パラメトリックなデータは、対になっていない両側スチューデントのｔ検定(unpaired two-tailed Student's t-test)、または一元配置分散分析(ANOVA)とpost-hoc Bonferroni's多重比較検定によってパラメトリックデータを分析した。Kruskal-Wallis ANOVAとその後のpost hoc Dunnett's多重比較検定を用いて、MWM試験でのプラットフォームの横断時間、穴掘りテストにおける餌ペレットの量、巣作りテストにおける巣作りスコアなどのノンパラメトリックデータを分析した。
9. Statistical analysis results were expressed as mean ± mean standard error (SEM) and statistically analyzed using
実施例1
HPLCクロマトグラフィーを用いてARH003およびARH004の分子特性を決定
本研究で用いられたベニクスノキタケ子実体は、クスノキ属牛楠(Cinnamomum kanehirae)木で栽培されたベニクスノキタケ子実体と高い植物相類似性指数(phytomic similarity index)を有する皿で培養されている(ARH003)である(Chung et al, 2016)。この類似性を確認するために、HPLCクロマトグラフィーを用いて、皿で培養されているベニクスノキタケ(ARH003)と切断木で培養されているベニクスノキタケ(ARH004)との成分を比較した(図1)。
Example 1
Molecular Properties of ARH003 and ARH004 Determined Using HPLC Chromatography The Camphor tree body used in this study has a high plant affinity index with that of the Camphor tree cultivated in the Cinnamomum kanehirae tree. It is cultured in a dish with (phytomic similarity index) (ARH003) (Chung et al, 2016). To confirm this similarity, HPLC chromatography was used to compare the components of the camphor tree (ARH003) cultured in a dish and the camphor tree (ARH004) cultured in a cut tree (Fig.). 1).
実施例2
ARH003は、APP/PS1マウスの大脳中のAβプラークを減少させた。
6ヶ月齢のAPP/PS1マウスでプラークが見られることは十分に確立されている(23)。したがって、3ヶ月齢のAPP/PS1雄雌または雌性マウスに、ビヒクルまたは100mg kg-1日-1のARH003を4ヶ月間経口投与し、Aβプラークの沈着(deposition)とグリア細胞の活性化に対するARH003の効果を研究した。ARH003投与中の体重変化を調査したところ、雄性マウスでは投与最終月にARH003が体重を有意に増加させたが、雌性マウスでは増加させなかった(図2)。
Example 2
ARH003 reduced Aβ plaques in the cerebrum of APP / PS1 mice.
It is well established that plaques are found in 6 month old APP / PS1 mice (23). Therefore, 3-month-old APP / PS1 males and females or female mice were orally administered vehicle or 100 mg kg -1 day -1 ARH003 for 4 months for Aβ plaque deposition and glial cell activation. The effect of was studied. When the change in body weight during ARH003 administration was investigated, ARH003 significantly increased body weight in the last month of administration in male mice, but not in female mice (Fig. 2).
実施例3
ARH003は、APP/PS1マウスの大脳中のグリア集団(glial cluster)を有するプラークの数を減少させる。
グリア集団を有するプラークの数に対するARH003の効果を評価した。APP/PS1トランスジェニックマウスの大脳中のグリア集団を有するプラークを判定するために、Amylo-glo染色、Iba-1およびGFAP免疫染色によって、Aβプラーク、ミクログリアおよびアストロサイトをそれぞれ検査した。その結果、ARH003で処置後、グリア集団を有するプラークの数が減少することがわかった(図3A～3E)。
Example 3
ARH003 reduces the number of plaques with glial clusters in the cerebrum of APP / PS1 mice.
The effect of ARH003 on the number of plaques with a Glia population was evaluated. Aβ plaques, microglia and astrocytes were tested by Amylo-glo staining, Iba-1 and GFAP immunostaining to determine plaques with glial populations in the cerebrum of APP / PS1 transgenic mice, respectively. As a result, it was found that the number of plaques having a glial population decreased after treatment with ARH003 (Figs. 3A to 3E).
実施例4
ARH003は、APP/PS1マウスの認知低下を回復させた。
穴掘り行動や巣作り行動は、脳の幅広い領域に作用し、これまでADトランスジェニックマウスのADLスキルの評価に応用されてきた。本研究では、3ヶ月齢のAPP/PS1マウスにARH003(100mg kg-1日)を114日間経口投与した。続いて、経口投与後84日目および86日目に穴掘りおよび巣作りのタスクを開始した(図4A)。APP/PS1マウスでは、自然発症穴掘り行動に欠陥が見られたが、ARH003を投与することで有意に回復した。APP/PS1マウスはまた、巣作りスコアと細断されていないネストレットによって評価された巣作り行動に欠陥が見られた。ARH003の投与により、障害された巣作り行動が有意に回復した(図4B)。
Example 4
ARH003 restored cognitive decline in APP / PS1 mice.
Digging and nesting behaviors affect a wide range of areas of the brain and have been applied to assess ADL skills in AD transgenic mice. In this study, ARH003 (100 mg kg -1 day) was orally administered to 3-month-old APP / PS1 mice for 114 days. Subsequently, digging and nesting tasks were initiated on days 84 and 86 after oral administration (Fig. 4A). In APP / PS1 mice, the spontaneous digging behavior was defective, but it was significantly recovered by administration of ARH003. APP / PS1 mice also showed defects in nesting scores and nesting behavior as assessed by unshredded nestlets. Administration of ARH003 significantly restored impaired nest-building behavior (Fig. 4B).
MWMタスクでは、APP/PS1マウスは訓練段階中、隠れたプラットフォームを見つけるまでの逃避潜時が長くなり、これは、APP/PS1マウスが7ヶ月齢で空間学習機能障害を現すことを示唆する。この明らかな機能障害は、ARH003の処理によって有意に回復した(図5A～5B)。二元配置反復測定(Two-way repeated measurement)ANOVA分析では、プラットフォームを見つけるまでの逃避潜時について、群と訓練日数の間の交互作用を確認した。訓練日数間、群間、対象間で有意差がある。Bonferroni posttestsでは、訓練3日目～6日目でビヒクルとARH003群との間で有意差がある。 In the MWM task, APP / PS1 mice have a longer escape latency to find a hidden platform during the training phase, suggesting that APP / PS1 mice exhibit spatial learning dysfunction at 7 months of age. This apparent dysfunction was significantly ameliorated by treatment with ARH003 (Figs. 5A-5B). Two-way repeated measurements ANOVA analysis confirmed the interaction between the group and training days for escape latency to find the platform. There are significant differences between training days, groups, and subjects. In Bonferroni posttests, there was a significant difference between the vehicle and the ARH003 group between the 3rd and 6th days of training.
プローブ試験では、APP/PS1マウスは、水泳速度に影響を与えることなく、標的ゾーンに到達するまでの潜時と標的ゾーンでの渡り時間が短縮された(図6A～6C)(データなし)。この場合も、ARH003の処理によって、この機能障害が有意に回復した。 In the probe test, APP / PS1 mice had reduced latency to reach the target zone and migration time in the target zone without affecting swimming speed (Figures 6A-6C) (no data). Again, treatment with ARH003 significantly improved this dysfunction.
参考文献
References
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4. Selkoe, D.J. Clearing the brain's amyloid cobwebs. Neuron. 2011, 232, 177-180.
5. Ryan, S.M.； Nolan, Y.M. Neuroinflammation negatively affects adult hippocampal neurogenesis and cognition: can exercise compensate? Neurosci. Biobehav. Rev. 2015, 61, 121-131.
6. Lee, I.S.； Jung, K.； Kim, I.S.； Park, K.I. Amyloid-β oligomers regulate the properties of human neural stem cells through GSK-3β signaling. Exp. Mol. Med. 2013, 45, e60.
7. Nicolas, M.； Hassan, B.A. Amyloid precursor protein and neural development. Development. 2014, 141, 2543-2548.
8. Sierra, A.； Beccari, S.； Diaz-Aparicio, I.； Encinas, J.M.； Comeau, S.； Tremblay, M,E. Surveillance, phagocytosis, and inflammation: how never-resting microglia influence adult hippocampal neurogenesis. Neural Plast. 2014, 2014, 610343.
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34. Deacon, R.M. Burrowing in rodents: a sensitive method for detecting behavioral dysfunction. Nat. Protoc. 2006, 1, 118-121.
35. Deacon, R.M. Assessing nest building in mice. Nat. Protoc. 2006, 1, 1117-1119.
36. Jirkof, P. Burrowing and nest building behavior as indicators of well-being in mice. J. Neurosci. Meth. 2014, 234, 139-146.
37. Woodbridge, R.； Sullivan, M.P.； Harding, E.； Crutch, S.； Gilhooly, K.J.； Gilhooly, M.； McIntyre, A.； Wilson, L. Use of the physical environment to support everyday activities for people with dementia: A systematic review. Dementia (London). 2016, pii: 1471301216648670.
38. Janus, C.； Flores, A.Y.； Xu, G.； Borchelt, D.R. Behavioral abnormalities in APPSwe/PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains. Neurobiol. Aging. 2015, 36, 2519-2532.
39. Tsai-Teng, T.； Chin-Chu, C.； Li-Ya, L.； Wan-Ping, C.； Chung-Kuang, L.； Chien-Chang, S.； Chi-Ying, H.F.； Chien-Chih, C.； Shiao, Y.J. Erinacine A-enriched Hericium erinaceus mycelium ameliorates Alzheimer's disease-related pathologies in APPswe/PS1dE9 transgenic mice. J. Biomed. Sci. 2016, 23, 49.
40. Hess, S.E.； Rohr, S.； Dufour, B.D.； Gaskill, B.N.； Pajor, E.A.； Garner, J.P. Home improvement: C57BL/6J mice given more naturalistic nesting materials build better nests. J. Am. Assoc. Lab. Anim. Sci. 2008, 47, 25-31.
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42. Chao, H.W.； Tsai, L.Y.； Lu, Y.L.； Lin, P.Y.； Huang, W.H.； Chou, H.J.； Lu, W.H.； Lin, H.C.； Lee, P.T.； Huang, Y.S. Deletion of CPEB3 enhances hippocampus-dependent memory via increasing expressions of PSD95 and NMDA receptors. J. Neurosci. 2013, 33, 17008-17022.
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44. Kim, T.K.； Han, H.E.； Kim, H.； Lee, J.E.； Choi, D.； Park, W.J.； Han, P.L. Expression of the plant viral protease NIa in the brain of a mouse model of Alzheimer's disease mitigates Abeta pathology and improves cognitive function. Exp. Mol. Med. 2012, 44, 740-748.
References
References
1. Hardy, J .; Selkoe, DJ The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002, 297, 353-356.
2. Fuster-Matanzo, A .; Llorens-Martin, M .; Hernandez, F .; Avila, J. Role of neuroinflammation in adult neurogenesis and Alzheimer disease: therapeutic approaches. Mediators Inflamm. 2013, 2013, 260925.
3. Winner, B .; Winkler, J. Adult neurogenesis in neurodegenerative diseases. Cold Spring Harb. Perspect Biol. 2015, 7, a021287.
4. Selkoe, DJ Clearing the brain's amyloid cobwebs. Neuron. 2011, 232, 177-180.
5. Ryan, SM; Nolan, YM Neuroinflammation negatively affects adult hippocampal neurogenesis and cognition: can exercise compensate? Neurosci. Biobehav. Rev. 2015, 61, 121-131.
6. Lee, IS; Jung, K .; Kim, IS; Park, KI Amyloid-β oligomers regulate the properties of human neural stem cells through GSK-3β signaling. Exp. Mol. Med. 2013, 45, e60.
7. Nicolas, M .; Hassan, BA Amyloid precursor protein and neural development. Development. 2014, 141, 2543-2548.
8. Sierra, A .; Beccari, S .; Diaz-Aparicio, I .; Encinas, JM; Comeau, S .; Tremblay, M, E. Surveillance, phagocytosis, and inflammation: how never-resting microglia influence adult hippocampal neurogenesis . Neural Plast. 2014, 2014, 610343.
9. Capsoni, S .; Tiveron, C .; Vignone, D .; Amato, G .; Cattaneo, A. Dissecting the involvement of tropomyosin-related kinase A and p75 neurotrophin receptor signaling in NGF deficit-induced neurodegeneration. Proc. Natl . Acad. Sci. USA. 2010, 107, 12299-12304.
10. Zhang, H .; Petit, GH; Gaughwin, PM; Hansen, C .; Ranganathan, S .; Zuo, X .; Smith, R .; Roybon, L .; Brundin, P .; Mobley, WC; Li JY NGF rescues hippocampal cholinergic neuronal markers, restores neurogenesis, and improves the spatial working memory in a mouse model of Huntington's Disease. J. Huntingtons Dis. 2013, 2, 69-82.
11. Jankowsky, JL; Fadale, DJ; Anderson, J .; Xu, GM; Gonzales. V .; Jenkins, NA; Copeland, NG; Lee, MK; Younkin, LH; Wagner, SL; Younkin, SG; Borchelt, DR Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum. Mol. Genet. 2004, 13, 159-170.
12. Malm, T .; Koistinaho, J .; Kanninen, K. Utilization of APPswe / PS1dE9 Transgenic Mice in Research of Alzheimer's Disease: Focus on Gene Therapy and Cell-Based Therapy Applications. Int. J. Alzheimers Dis. 2011, 2011 , 517160.
13. Volianskis, A .; Kostner. R .; Molgaard, M .; Hass, S .; Jensen, MS Episodic memory deficits are not related to altered glutamatergic synaptic transmission and plasticity in the CA1 hippocampus of the APPswe / PS1deltaE9-deleted transgenic mice model of β-amyloidosis. Neurobiol. Aging 2010, 31, 1173-1187.
14. Reiserer, RS; Harrison, FE; Syverud, DC; McDonald, MP Impaired spatial learning in the APPSwe + PSEN1DeltaE9 bigenic mouse model of Alzheimer's disease. Genes Brain Behav. 2007, 6, 54-65.
15. Xiong, H .; Callaghan, D .; Wodzinska, J .; Xu, J .; Premyslova, M .; Liu, QY; Connelly, J .; Zhang, W. Biochemical and behavioral characterization of the double transgenic mouse model (APPswe / PS1dE9) of Alzheimer's disease. Neurosci. Bull. 2011, 27, 221-232.
16. Hamilton, A .; Holscher, C. The effect of aging on neurogenesis and oxidative stress in the APP (swe) / PS1 (deltaE9) mouse model of Alzheimer's disease. Brain Res. 2012, 1449, 83-93.
17. Wu, SH .; Ryvarden L ,; Chang, TT Antrodia camphorata ("niu-chang-chih"), new combination of a medicinal fungus in Taiwan. Bot. Bull. Acad. Sin. 1997, 38, 273-275 ..
18. Peng, CC ,; Chen, KC; Peng, RY; Chyau, CC; Su, CH ,; Hsieh-Li, HM Antrodia camphorata extract induces replicative senescence in superficial TCC, and inhibits the absolute migration capability in invasive bladder carcinoma cells . J. Ethnopharmacol. 2007, 109, 93-103.
19. Chen, CC; Shiao, YJ; Lin, RD; Shao, YY; Lai, MN; Lin, CC; et al., Neuroprotective diterpenes from the fruiting body of Antrodia camphorata. J. Nat. Prod. 2006, 69, 689-691.
20. Phan, CW; David, P .; Naidu, M .; Wong, KH; Sabaratnam, V. Therapeutic potential of culinary-medicinal mushrooms for the management of neurodegenerative diseases: diversity, metabolite, and mechanism. Crit. Rev. Biotechnol . 2015, 35, 355-368.
21. Yue, PY; Wong, YY; Wong, KY; Tsoi, YK; Leung, KS Current evidence for the hepatoprotective activities of the medicinal mushroom Antrodia cinnamomea. Chin. Med. 2013,8, 21.
22. Geethangili, M .; Tzeng, YM Review of Pharmacological Effects of Antrodia camphorata and Its Bioactive Compounds. Evid. Based Complement. Alternat. Med. 2011, 2011, 212641.
23. Yan, P .; Hu, X .; Song, H .; Yin, K .; Bateman, RJ; Cirrito, JR; Hsu, FF; Turk, JW; Xu, J .; Hsu, CY; Holtzman, DM Lee, JM Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J. Biol. Chem. 2006, 281, 24566-24574.
24. Vepsalainen, S .; Koivisto, H .; Pekkarinen, E .; Makinen, P .; Dobson, G .; McDougall, GJ; Stewart, D .; Haapasalo, A .; Karjalainen, RO; Tanila, H .; Hiltunen, M. Anthocyanin-enriched bilberry and blackcurrant extracts modulate amyloid precursor protein processing and alleviate behavioral abnormalities in the APP / PS1 mouse model of Alzheimer's disease. J. Nutr. Biochem. 2013, 24, 360-370.
25. Mawuenyega, KG; Sigurdson, W .; Ovod, V .; Munsell, L .; Kasten, T .; Morris, JC; Yarasheski, KE; Bateman, RJ Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science. 2010, 330, 1774.
26. Qiu, WQ; Folstein, MF Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiol. Aging. 2006, 27, 190-198.
27. Baranello, RJ; Bharani, KL; Padmaraju, V .; Chopra, N .; Lahiri, DK; Greig, NH; Pappolla, MA; Sambamurti, K. Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer's disease. Curr. Alzheimer Res. 2015, 12, 32-46.
28. Serrano-Pozo, A .; Muzikansky, A .; Gomez-Isla, T .; Growdon, JH; Betensky, RA; Frosch, MP; Hyman, BT Differential relationships of reactive astrocytes and microglia to fibrillar amyloid deposits in Alzheimer disease . J. Neuropathol. Exp. Neurol. 2013, 72, 462-471.
29. Fu, AK; Hung, KW; Yuen, MY; Zhou, X .; Mak, DS; Chan, IC; Cheung, TH; Zhang, B .; Fu, WY; Liew, FY; Ip, NY IL-33 ameliorates Alzheimer's disease-like pathology and cognitive decline. Proc. Natl. Acad. Sci. USA. 2016, 113, E2705-E2713.
30. El Khoury, J .; Toft, M .; Hickman, SE; Means, TK; Terada, K .; Geula, C .; Luster, AD Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nat. Med. 2007, 13, 432-438.
31. Goto, Y .; Niidome, T .; Hongo, H .; Akaike, A .; Kihara, T .; Sugimoto, H. Impaired muscarinic regulation of excitatory synaptic transmission in the APPswe / PS1dE9 mouse model of Alzheimer's disease. Eur . J. Pharmacol. 2008, 583, 84-91.
32. Yeh, CW; Yeh, SH; Shie, FS; Lai, WS; Liu, HK; Tzeng, TT; Tsay, HJ; Shiao, YJ Impaired cognition and cerebral glucose regulation are associated with astrocyte activation in the parenchyma of metabolically stressed APPswe / PS1dE9 mice. Neurobiol. Aging 2015, 36, 2984-2994.
33. Duan, S .; Guan, X .; Lin, R .; Liu, X .; Yan, Y .; Lin, R .; Zhang, T .; Chen, X .; Huang, J .; Sun, X .; Li, Q .; Fang, S .; Xu, J .; Yao, Z .; Gu, H. Silibinin inhibits acetylcholinesterase activity and amyloid β peptide aggregation: a dual-target drug for the treatment of Alzheimer's disease. Neurobiol. Aging 2015, 36, 1792-1807.
34. Deacon, RM Burrowing in rodents: a sensitive method for detecting behavioral dysfunction. Nat. Protoc. 2006, 1, 118-121.
35. Deacon, RM Assessing nest building in mice. Nat. Protoc. 2006, 1, 1117-1119.
36. Jirkof, P. Burrowing and nest building behavior as indicators of well-being in mice. J. Neurosci. Meth. 2014, 234, 139-146.
37. Woodbridge, R .; Sullivan, MP; Harding, E .; Crutch, S .; Gilhooly, KJ; Gilhooly, M .; McIntyre, A .; Wilson, L. Use of the physical environment to support everyday activities for people with dementia: A systematic review. Dementia (London). 2016, pii: 1471301216648670.
38. Janus, C .; Flores, AY; Xu, G .; Borchelt, DR Behavioral abnormalities in APPSwe / PS1dE9 mouse model of AD-like pathology: comparative analysis across multiple behavioral domains. Neurobiol. Aging. 2015, 36, 2519- 2532.
39. Tsai-Teng, T .; Chin-Chu, C .; Li-Ya, L .; Wan-Ping, C .; Chung-Kuang, L .; Chien-Chang, S .; Chi-Ying, HF; Chien-Chih, C .; Shiao, YJ Erinacine A-enriched Hericium erinaceus mycelium ameliorates Alzheimer's disease-related pathologies in APPswe / PS1dE9 transgenic mice. J. Biomed. Sci. 2016, 23, 49.
40. Hess, SE; Rohr, S .; Dufour, BD; Gaskill, BN; Pajor, EA; Garner, JP Home improvement: C57BL / 6J mice given more naturalistic nesting materials build better nests. J. Am. Assoc. Lab. Anim. Sci. 2008, 47, 25-31.
41. Morris, R. Developments of a water-maze procedure for studying spatial learning in the rat. J. Neurosci. Methods. 1984, 11, 47-60.
42. Chao, HW; Tsai, LY; Lu, YL; Lin, PY; Huang, WH; Chou, HJ; Lu, WH; Lin, HC; Lee, PT; Huang, YS Deletion of CPEB3 enhances hippocampus-dependent memory via increasing expressions of PSD95 and NMDA receptors. J. Neurosci. 2013, 33, 17008-17022.
43. Wang, LS; Zhou, J .; Shao, XM; Tang, XC Huperzine A emitters cognitive deficits and brain injury in neonatal rats after hypoxia-ischemia. Brain Res. 2002, 949, 162-170.
44. Kim, TK; Han, HE; Kim, H .; Lee, JE; Choi, D .; Park, WJ; Han, PL Expression of the plant viral protease NIa in the brain of a mouse model of Alzheimer's disease mitigates Abeta pathology and improves cognitive function. Exp. Mol. Med. 2012, 44, 740-748.
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| JP (1) | JP2022511785A (en) |
| CN (1) | CN113453689A (en) |
| AU (1) | AU2019387473A1 (en) |
| TW (1) | TW202038981A (en) |
| WO (1) | WO2020113146A1 (en) |
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| TW202038981A (en) * | 2018-11-28 | 2020-11-01 | 薩摩亞商吉亞生技控股股份有限公司 | Composition and method for treating dementia |
| CN113350360A (en) * | 2021-06-18 | 2021-09-07 | 西南医科大学 | Novel application of triterpenic acid compound as A beta fiber formation inhibitor drug |
| TWI779875B (en) * | 2021-10-13 | 2022-10-01 | 健裕生技股份有限公司 | Compounds for preventing nerve damage and protecting nerves, methods for their preparation, medicinal products and uses thereof |
| US11987566B2 (en) | 2022-01-28 | 2024-05-21 | Genhealth Pharma Co., Ltd. | Nerve damage preventing and nerve protecting compounds, preparation method thereof, pharmaceutical composition thereof, and their use |
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| US7601854B2 (en) * | 2006-10-25 | 2009-10-13 | Kang Jian Biotech Corp., Ltd. | Diterpenes from the fruiting body of Antrodia camphorata and pharmaceutical compositions thereof |
| EP2922534B1 (en) * | 2012-11-21 | 2020-04-08 | Golden Biotechnology Corporation | Methods and compositions for treating neurodegenerative diseases |
| TWI623749B (en) * | 2015-04-30 | 2018-05-11 | 吳永昌 | Preparation method and analytic method for the extract of androdia cinnamomea |
| TW201733573A (en) * | 2016-03-25 | 2017-10-01 | Ying-Yu Guo | Use of Antrodia camphorata compound for manufacturing medicament in treating and preventing neurodegenerative diseases having the compound represented by formula I with R1 being hydrogen or an acetyl group |
| CN107296805A (en) * | 2016-04-14 | 2017-10-27 | 郭盈妤 | Antrodia camphorata compound and its extract are used for the purposes for preparing the medicine for the treatment of and prevention of neurodegenerative diseases |
| CN106727898B (en) * | 2017-02-21 | 2020-07-31 | 阮时宝 | Pharmaceutical composition for preventing and treating Alzheimer disease and preparation method thereof |
| TW202038981A (en) * | 2018-11-28 | 2020-11-01 | 薩摩亞商吉亞生技控股股份有限公司 | Composition and method for treating dementia |
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2019
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- 2019-11-29 EP EP19890710.7A patent/EP3886862A4/en active Pending
- 2019-11-29 WO PCT/US2019/063831 patent/WO2020113146A1/en unknown
- 2019-11-29 AU AU2019387473A patent/AU2019387473A1/en active Pending
- 2019-11-29 US US16/699,377 patent/US20200164010A1/en active Pending
- 2019-11-29 CN CN201980077854.0A patent/CN113453689A/en active Pending
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| US20200164010A1 (en) | 2020-05-28 |
| EP3886862A4 (en) | 2022-10-26 |
| CN113453689A (en) | 2021-09-28 |
| WO2020113146A1 (en) | 2020-06-04 |
| EP3886862A1 (en) | 2021-10-06 |
| TW202038981A (en) | 2020-11-01 |
| AU2019387473A1 (en) | 2021-07-01 |
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